Routes of Resistance

More than One Answer

In the classic militaristic interpretation, antibiotics exist to target competitors, and resistance genes evolve to protect producers. But here again, we might do well to remember that massive concentrations of antibiotics used in clinical settings, and the consequences of such massive use, may be obscuring subtler phenomena in the microbial world. A second effect, which I will call the Pete Townshend effect, may also underlie some of the evolution of resistance. In this scenario, antibiotics are playing their signaling role, but the levels of this signal molecule are so high in and around the producing cell that they will cause unintended damage as a byproduct of their high concentration. Resistance evolves in producer strains to protect them from the damaging consequences of overwhelming signal strength. As the antibiotic diffuses away from the producer, its concentration declines. The antibiotic loses its lethality and regains its signaling function. If antibiotics have multiple meanings, resistance too must mean more than one thing.

Our ability to examine the genomes of both culturable and unculturable organisms has changed the way we look at the origin of antibiotic resistance mechanisms. Resistance is everywhere, and we don’t always know why. We now realize, for example, that the bacteria in a gram of soil harbor hundreds of different genes that can, in the right setting, contribute to resistance. For instance, work by Gerard D. Wright of McMaster University and others, reveals that bacteria in the soil already harbor the rudiments of resistance to all known antibiotics, including entirely synthetic antibiotics with no counterpart in the natural world. Virtually every bacterial cell in these environmental samples is, on average, resistant to eight antibiotics.

The collection of mechanisms responsible for resistance in these soil bacteria has come to be called the “environmental resistome” (as it rhymes, as everything must nowadays, with “genome”). The samples used to investigate the resistome are not ones where clinical strains selected for resistance might be congregating (although wastewater streams from hospitals and water treatment plants in large cities harbor their own impressive collection of clinic-selected resistant strains). Instead, virtually every sample used has a stable microbial ecosystem that has never been exposed to clinical levels of antibiotics and has not been in contact with resistant clinical bacterial cultures. Nonetheless, every one of the samples harbors a vast repository of resistance genes.

This environmental resistome provides a glimpse of the raw materials that clinical pathogens have accessed in the antibiotic age. What is sobering about the discovery of the resistome is the revelation that the microbial world already possesses a functional arsenal of defenses against the antibiotics we develop for clinical use. The resistome also demands a subtle, but critical, change in our perspective on resistance: Many of the mechanisms involved in so-called resistance may be playing other critical roles in cells coexisting peacefully with their neighbors. If antibiotics at sublethal doses really are signal molecules, perhaps resistance is really a signal modulator, altering the meaning and modifying the effects of the message on the recipient cell. Once again, the context in which we usually first encounter resistance mechanisms—in clinical infections as they become insensitive to therapeutic doses of antibiotics—may be obscuring the many roles these mechanisms play in the microbial world.